Disrupted proteostasis can lead to the accumulation of damaged proteins and protein aggregates and a loss of correlation between mRNA and corresponding protein levels. These effects are hallmarks of aging in the brain; however, how these hallmarks are functionally connected to each other and other hallmarks, such as DNA damage and reduced transcription, is unclear. Now, Di Fraia, Marino, Lee et al. have combined ribosome and transcriptome profiling and proteomics analysis of killifish — chosen for their short lifespan and conserved aging brain phenotypes — to investigate the mechanisms and consequences of this ‘protein–transcript decoupling’.

The team found that proteins with a large amount of basic residues, particularly those involved in DNA and RNA binding and repair, were decreased in concentration relative to their transcript abundance as the killifish aged. The team also identified decreased levels of ribosomal proteins, which are also rich in polybasic stretches, independent of mRNA changes. Aging affected mitochondrial respiratory chain proteins in an opposite way, with a decrease in transcript abundance but little change in corresponding protein levels.